Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen

Wurster, Claudia D.; Steinacker, Petra; Günther, René; Koch, Jan Christoph; Lingor, Paul; Uzelac, Zeljko; Witzel, Simon; Wollinsky, K. H.; Winter, Benedikt; Osmanovic, Alma; Schreiber‐Katz, Olivia; Shweiki, Rami Al; Ludolph, Albert C.; Petri, Susanne; Hermann, Andreas; Otto, Markus; MND-Net,

doi:10.1007/s00415-019-09547-y

Cited by 54 publications

(69 citation statements)

References 33 publications

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“…Clinical trials which could address this issue require long durations and robust clinical outcome measures, drawing attention to the need for biomarkers which are sensitive to changes in disease progression and/or response to disease modifying agents [120]. Unlike studies in infants and children with SMA, in which circulating neurofilaments are emerging as potential measures to assess disease progression and response to nusinersen treatment [121], no studies in adults with SMA have yielded a robust, reliable measurement [86,88,[122][123][124][125][126]. A potential complexity in trying to detect elevated markers of axonal degradation in adults with SMA is again the slow rate of progression.…”

Section: Discussionmentioning

confidence: 99%

Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review

Wan

Carey

D’Silva

et al. 2020

Orphanet J Rare Dis

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Background: Spinal muscular atrophy (SMA) is a neurodegenerative disease that has a substantial and multifaceted burden on affected adults. While advances in supportive care and therapies are rapidly reshaping the therapeutic environment, these efforts have largely centered on pediatric populations. Understanding the natural history, care pathways, and patient-reported outcomes associated with SMA in adulthood is critical to advancing health policy, practice and research across the disease spectrum. The aim of this study was to systematically review research investigating the healthcare, well-being and lived experiences of adults with SMA. Methods: In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analysis guidelines, seven electronic databases were systematically searched until January 2020 for studies examining clinical (physical health, natural history, treatment) and patient-reported (symptoms, physical function, mental health, quality of life, lived experiences) outcomes in adults with SMA. Study risk of bias and the level of evidence were assessed using validated tools. Results: Ninety-five articles met eligibility criteria with clinical and methodological diversity observed across studies. A heterogeneous clinical spectrum with variability in natural history was evident in adults, yet slow declines in motor function were reported when observational periods extended beyond 2 years. There remains no high quality evidence of an efficacious drug treatment for adults. Limitations in mobility and daily activities associated with deteriorating physical health were commonly reported, alongside emotional difficulties, fatigue and a perceived lack of societal support, however there was no evidence regarding effective interventions. Conclusions: This systematic review identifies the many uncertainties regarding best clinical practice, treatment response, and long-term outcomes for adults with SMA. This comprehensive identification of the current gaps in knowledge is essential to guide future clinical research, best practice care, and advance health policy with the ultimate aim of reducing the burden associated with adult SMA.

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Section: Discussionmentioning

confidence: 99%

Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review

Wan

Carey

D’Silva

et al. 2020

Orphanet J Rare Dis

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“…In a large case series of infants affected by type 1 SMA, plasma pNfH levels were manifold higher than in healthy controls [76]. However, studies collecting NF levels in later-onset SMA type 2 and 3 revealed no substantial differences in NfL and pNfH concentrations between patients and healthy controls in both serum and CSF [77,78].…”

Section: Nfs As Diagnostic Biomarkers In Als and Other Mndsmentioning

confidence: 96%

“…Moreover, younger-onset infants had reduced cMAP at baseline, pointing to a correlation between pNfH and markers of disease severity [77] These results were confirmed in a small group of type 1 SMA infants where NfL measured in CSF (collected at the time of lumbar puncture for ASO administration), starting from baseline peak levels, normalized between the fourth and fifth dose of Nusinersen, and the decrease in its levels correlated with improvement in motor function [101]. However, studies in SMA types 2 and 3 showed that NF levels did not differ between patients and controls in both CSF and serum, and their concentrations do not substantially modify during intrathecal therapy with ASO [77,78].…”

Section: Nfs As Disease-progression Biomarkersmentioning

confidence: 99%

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Zucchi

Bonetto

Sorarù

et al. 2020

Mol Neurodegeneration

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Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today’s MND research agenda. In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood. In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic.

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“…In particular, the phosphorylation, abundant on the NF-H, ensures protection from degradation [ 133 ]. Although NFs seem to be reliable biomarkers for SMA infants, as their level is reduced upon Nusinersen treatment and this is generally correlated with an improved motor function [ 134 ], few recent publications have described contradicting results for the use of NFs as biomarkers for adult SMA patients’ response to therapy [ 29 , 135 ]. Eleven SMA type 3 patients (all adults—38.5 years mean age) analyzed for their pNF-H content in blood and CSF showed no change after administration of the Nusinersen loading doses [ 136 ].…”

Section: Molecular Biomarkersmentioning

confidence: 99%

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

Smeriglio

Langard

Querin

et al. 2020

JPM

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Spinal muscular atrophy (SMA) is currently classified into five different subtypes, from the most severe (type 0) to the mildest (type 4) depending on age at onset, best motor function achieved, and copy number of the SMN2 gene. The two recent approved treatments for SMA patients revolutionized their life quality and perspectives. However, upon treatment with Nusinersen, the most widely administered therapy up to date, a high degree of variability in therapeutic response was observed in adult SMA patients. These data, together with the lack of natural history information and the wide spectrum of disease phenotypes, suggest that further efforts are needed to develop precision medicine approaches for all SMA patients. Here, we compile the current methods for functional evaluation of adult SMA patients treated with Nusinersen. We also present an overview of the known molecular changes underpinning disease heterogeneity. We finally highlight the need for novel techniques, i.e., -omics approaches, to capture phenotypic differences and to understand the biological signature in order to revise the disease classification and device personalized treatments.

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Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen

Cited by 54 publications

References 33 publications

Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review

Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

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